Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

• This invention relates to a method for preparing D 5 According to this process, a natural penicillin, specifa-amino-benzylpenicillin (I) ically benzylpenicillin or phenoxymethylpenicillin, is
• ester preferably with trimethyl silyl chloride or dimethyldichlorosilane in the presence of a tertiary base, CH preferably quinoline or dimethyl aniline in order to ob- -CH-CO-NH 3 l0 tain an ester which can be easily hydrolized also at a room temperature.
• This ester is then transformed into the imidate (ll) according to a well known reaction of amides (R. Roger D. G. Neilson The Chemistry of Imidates in Chemical Reviews 61, 179, l96l), by adding to the COOH ester solution at temperatures from 10 C to 50 C first a chlorinating agent, preferably PCI in equimolar amount to form an imino chloride, then a lower pridirectly from natural penicillins as benzylpenicillin or ar alcohol, preferably butanol. phenoxymethylpenicillin by a single-stage process.
• This reaction is carried out in an organic solvent,
• the Wide applications of (l) 115 antibiotic in u a preferably acetone or chlorinated solvents or a mixture therapy are well known.
• the object of the present invention is to provide a wherein method for the production of D ()-0z- R CH C. ,H C H C H,, aminobenzylpenicillin from natural penicillins by a di- R Si(CH Si(CH Cl rect process not involving isolation of intermediates.
• a further object of the present invention is to provide ranging from C to -l0 C in order to minimize the a method for preparing (I) easy to e accomplished, o SO hydrolysis ofthe acid chloride (III) which can therefore rapid execution, which requires a very simple equipreact with the intermediate (A) resulting from the addiment and which furnishes a high conversion yield. tion of water to imidate (ref. cited).
• Still another object is to have a process which can be It will be clear to those skilled in art that the synthesis carried out also in a single solvent, namely acetone, of the penicillin (I) from the imidate (ll) does not necthus providing a further simplification. essarily involve o-aminopenicillanic acid as intermedi'.
• the ate because the formation of(l) can be correctly interpresent invention by transforming an ester of a natural preted b a conc rted m chanism b twe (A) d penicillin into an imidate, which by addition of the (III) as shown in the following scheme:
• the pH of the aqueous layer is adjusted to 4 5 to precipitate D()-a-aminobenzylpenicillin as trihydrate.
• benzylpenicillin potassium salt 75 g are suspended in 800 ml of acetone at room temperture. 100 g of quinoline technical grade and 44 g of dimethyldichlorosilane are added. After standing one hour under stirring at room temperature the solution is cooled to 30 C; then 42.5 g of PCl are added.
• the suspension is filtered to eliminate the impurities. 400 ml of deionized water and 1000 ml of chloroform are added.
• the starting material is fermentation broth obtained from a mutant culture of penicillinchrysogenum.
• the fermentation medium having the following composition (gr./liter):
• the fermentation broth has a potency of about 8 mg/ml as benzyl penicillin.
• the broth is filtered on celite, then acidified until pH 2 and extracted with chloroform.
• the benzyl penicillin is extracted from chloroform with water buffered at pH 7 and then riextracted with fresh chloroform after acidification of aqueous solution.
• the organic layer is washed with water, dried with sodium sulphate and after filtration evaporated under vacuum until to have a solution with a concentration of about 10 percent as benzyl penicillin.
• 75 g of benzyl penicillin potassium salt are suspended in 800 ml of methylene chloride freshly distilled, 200 g of quinoline technical grade and 40 g of trimethyl chlorosilane are added. After stirring for 30 min. at room temperature the solution is cooled to -40 C and g of PCI,, are added. After stirring for 2 hours maintaining the temperature below 20 C, g of methyl ene chloride containing 7 g of methyl alcohol are added. The solution is kept for two hours at about -20 C under stirring, then 400 ml of acetone containing 1 percent of water and 68 g of chloride of D()-aphenylglycine hydrochloride are added. The solution is stirred for 40 minutes at -20 C and then for 20 min- .utes at -l5 C. 600 ml of deionized water are added,
• the pH is corrected to 1.5 with NaOH 5 percent and the solution is filtered. After separation of two layers, the organic one is discarded; the pH is brought to 7.6 and the aqueous solution is washed with 600 ml of chloroform.
• 78 g of phenoxymethylpenicillin potassium salt are suspended in 600 ml of acetone containing 250 g of dimethylaniline; after stirring for l0 minutes 40 g of trimethylchlorosilane are added. The solution is cooled to 40 C and a suspension of 45 g of PCl,-, in 200 m] of methylene chloride is slowly added. After stirring for 2 hours maintaining the temperature at about 20 C. 400 ml of chloroform containing 16 g of butyl alcohol are added. The solution is kept under stirring for 3 hours at 20 C. Then 40 ml of acetone containing 10 percent by volume of water is dropwise added and simultaneously also 46 g of chloride of D()-aphenylglycine are added by small portions.
• the suspension is filtered, 500 ml of deionized water are added and the pH is brought to 1.8 by adding sodium hydroxide 3 percent.
• benzylpenicillin potassium salt g are suspended in 800ml of chloroform at room temperature.
• g of quinoline technical grade and 40 g of dimethyldichlorosilane are added.
• the solution is cooled to -30 C.
• 42,5 g of PCl are added and the solution is maintained at 30 C under stirring for 3 hours.
• 250 ml of butylalcohol previously cooled at 3() C are added and the solution stirred for 4 hours always at -30 C.
• the temperature is raised to 25 C and 40 ml of acetone containing 5 ml of water are added.
• a method for preparing D()-aaminobenzylpenicillin directly from natural penicillins comprising the steps of:
• a natural penicillin selected from a group consisting of benzylpenicillin, phenoxymethylpenicillin, and combinations of benzylpenicillin and phenoxymethylpenicillin in a solvent selected from a group consisting of methylene chloride, chloroform, acetone, and combinations of methylene chloride, chloroform and acetone;
• alkychlorosilane selected from the group consisting of dimethyldichlorosilane and trimethylchlorosilane, and a tertiary base selected from the group consisting of dimethylaniline and quinoline to esterity said natural penicillin;
• a primary alcohol selected from the group consisting of methyl alcohol and butyl alcohol to transform the iminochloride into an imidate
• a method for preparing D()-aaminobenzylpenicillin directly from natural penicillins comprising the steps of:
• a natural penicillin selected from a group 0011- sisting of benzylpenicillin, phenoxymethylpenicillin, and combinations of benzylpenicillin and phenomethylpenicillin in a solvent selected from a group consisting of methylene chloride, chloroform, acetone, and combinations of methylene chloride, chloroform, and acetone;
• alkychlorosilanc selected from the group consisting of dimethylchlorosilane and trimethylchlorosilane and a tertiary base selected from the group consisting of dimethylaniline and quinoline to esterity said natural penicillin;
• a primary alcohol selected from the group consisting of methyl alcohol and butyl alcohol to transform the iminochloride into an imidate

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)

Applications Claiming Priority (1)

Publications (1)

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ID=11219128

Family Applications (1)

Country Status (14)

Citations (2)

• 1971
  • 1971-11-26 GB GB5496771A patent/GB1344309A/en not_active Expired
  • 1971-12-28 NL NL7117953A patent/NL7117953A/xx unknown
• 1972
  • 1972-01-22 ES ES399098A patent/ES399098A1/es not_active Expired
  • 1972-01-28 ZA ZA720567A patent/ZA72567B/xx unknown
  • 1972-06-12 US US262123A patent/US3872088A/en not_active Expired - Lifetime
  • 1972-06-19 CA CA145,118A patent/CA980764A/en not_active Expired
  • 1972-06-22 LU LU65588D patent/LU65588A1/xx unknown
  • 1972-06-22 AT AT538972A patent/AT320146B/de not_active IP Right Cessation
  • 1972-06-23 CH CH950772A patent/CH579573A5/xx not_active IP Right Cessation
  • 1972-06-23 BE BE785376A patent/BE785376A/xx unknown
  • 1972-06-23 AU AU43863/72A patent/AU461848B2/en not_active Expired
  • 1972-06-23 AR AR242725A patent/AR192801A1/es active
  • 1972-06-24 DE DE2231072A patent/DE2231072A1/de active Pending
  • 1972-06-26 PH PH13661A patent/PH10806A/en unknown

Patent Citations (2)

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